Methamphetamine (MA)-induced toxicity requires several components, including increased extracellular levels of striatal dopamine and glutamate, and hyperthermia. The primary objective of this proposal is to examine the interaction between body temperature and receptor activation in MA treated rats, and their specific roles in mediating MA-induced neurotransmitter release and neurotoxicity. These studies will also investigate the circuitry involved in mediating lasting neurotransmitter depletions following MA administration. The role of hyperthermia in mediating neurotransmitter release, free radical formation, and lasting dopamine depletions following MA will be examined by infusing the drug directly into discrete brain regions in combination with exposure to hyperthermia. The role of specific dopamine and glutamate receptor activation will be investigated by infusing a D1, D2, or NMDA antagonist directly into discrete brain regions during systemic administration of MA. Determination of specific (i.e., receptor) and non-specific (i.e., hyperthermic) events mediating MA-induced striatal damage would help to elucidate the mechanisms underlying neurodegenerative processes in general. In addition, these studies may identify critical stages in the neurotoxic cascade leading to nerve terminal death following MA exposure. Understanding the consequences of psychostimulant administration is especially crucial given the recent evidence of DA terminal loss in human MA abusers and the proposal that MA-toxicity may be a model for preclinical Parkinson's disease.